Compounds having fungicidal activity and processes to make and use same

ABSTRACT

A compound according to formula one that is useful as a fungicide is provided. Additionally, processes to make and use same are provided.

PRIORITY

This application is a 371 of PCT/US01/44032, filed Nov. 16, 2001, whichclaims benefit of 60/249,653, filed Nov. 17, 2000.

FIELD OF THE INVENTION

This invention is related to the field of compounds having fungicidalactivity and processes to make and use such compounds.

BACKGROUND OF THE INVENTION

Our history is riddled with outbreaks of fungal diseases that havecaused widespread human suffering. One need look no further than theIrish potato famine, which occurred from 1845 to 1860, where anestimated 1,000,000 people died, and an estimated 1,500,000 peopleemigrated, to see the effects of a fungal disease. Fungicides arecompounds, of natural or synthetic origin, which act to protect plantsagainst damage caused by fungi. Current methods of agriculture relyheavily on the use of fungicides. In fact, some crops cannot be grownusefully without the use of fungicides. Using fungicides allows a growerto increase the yield and the quality of the crop and consequently,increase the value of the crop. In most situations, the increase invalue of the crop is worth at least three times the cost of the use ofthe fungicide. However, no one fungicide is useful in all situations.Consequently, research is being conducted to produce fungicides that aresafer, that have better performance, that are easier to use, and thatcost less. In light of the above, the inventors provide this invention.

SUMMARY OF THE INVENTION

It is an object of this invention to provide compounds that havefungicidal activity. It is an object of this invention to provideprocesses that produce compounds that have fungicidal activity. It is anobject of this invention to provide processes that use compounds thathave fungicidal activity. In accordance with this invention, processesto make and processes to use compounds having a general formulaaccording to formula one, and said compounds are provided. While all thecompounds of this invention have fungicidal activity, certain classes ofcompounds may be preferred for reasons such as, for example, greaterefficacy or ease of synthesis.

Throughout this document, all temperatures are given in degrees Celsiusand all percentages are weight percentages, except for percent yieldswhich are mole percentages, unless otherwise stated. The term “alkyl”,“alkenyl”, or “alkynyl” refers to an unbranched, or branched, chaincarbon group. The term “alkoxy” refers to an unbranched, or branched,chain alkoxy group. The term “haloalkyl” refers to an unbranched, orbranched, alkyl group substituted with one or more halo atoms, definedas F, Cl, Br, and I. The term “haloalkoxy” refers to an unbranched, orbranched, chain alkoxy group substituted with one or more halo atoms.The term “alkoxylalkyl” refers to an unbranched, or branched, chainalkyl group substituted with one or more alkoxy groups. The term“alkoxyalkoxy” refers to an unbranched, or branched, chain alkoxy groupsubstituted with one or more alkoxy groups. The term “aryl” refers to aphenyl or naphthyl group. The term “Me” refers to a methyl group. Theterm “Et” refers to an ethyl group. The term “Pr” refers to a propylgroup. The term “Bu” refers to a butyl group. The term “EtOAc” refers toethyl acetate. The term “ppm” refers to parts per million. The term,“psi” refers to pounds per square inch.

Heteroaryl is defined by the following Formula Two

wherein 2A represents a 5- or 6-membered ring and 2B represents a 9- or10-membered fused bicyclic ring in which each of X₁-X₅ is independentlya bond, O, S, NR⁷, N, or CR, where R is selected from the groupconsisting of halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ alkoxy,C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₁₋₄ alkoxyalkyl, C₁₋₄ alkoxyalkoxy,CN, NO₂, OH, SCN, C(═O)R⁶, C(═NR⁶)R⁶, S(O_(n))R⁶ where n=0, 1 or 2,aryl, aryloxy, heteroaryl, and heteroaryloxy, and where no more than oneof X₁-X₅ is O, S, or NR⁷, no more than one of X₁-X₅ is a bond, when anyone of X₁-X₅ is S, O or NR⁷, one of the adjacent X₁-X₅ must represent abond; and at least one of X₁-X₅ must be O, S, NR⁷ or N.

Examples of such heteroaryls are pyridinyl, pyridazinyl, pyrimidinyl,pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, quinolinyl, isoquinolinyl,phthalazinyl, quinazolinyl, quinoxalinyl, cinnolinyl, indolyl,isoindolyl, indazolyl, thienyl, benzothienyl, furanyl, benzofuranyl,thiazolyl, benzothiazolyl, isothiazolyl, benzoisothiazolyls, oxazolyl,benzoxazolyl, isoxazolyl, and benzoisoxazolyl.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of this invention have a formula according to formula one.

In formula one:

R¹ is selected from the group consisting of F, Cl, Br, CN, C₁₋₄ alkyl,C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxyalkyl, C₃-C₆cycloalkyl, C₃-C₆ cycloalkenyl, CH₂(C═O)R⁵, and CH₂CN;

R² and R³ are selected from the group consisting of H, CH₃, F, and Cl;

R⁴ is selected from the group consisting of C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkenyl, aryl, and heteroaryl,where said alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl, can besubstituted with one or more substituents selected from the groupconsisting of halo, C₁₋₄ alkoxy, C₃₋₆ cycloalkyl, aryl and heteroaryl,and where said aryl and heteroaryl can be substituted with one or moresubstituents selected from the group consisting of halo, C₁₋₄ alkyl,C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄haloalkoxy, C₁₋₄ alkoxyalkyl, C₁₋₄ alkoxyalkoxy, CN, NO₂, OH, SCN,C(═O)R⁶, C(═NR⁶)R⁶, S(ON)R⁶ where n=0, 1 or 2, aryl, aryloxy,heteroaryl, and heteroaryloxy;

R⁵ is selected from the group consisting of H, OR⁷, and C₁₋₄ alkyl;

R⁶ is selected from the group consisting of H, C₁₋₄ alkyl, C₂₋₄ alkenyl,C₂₋₄ alkynyl, C₁₋₄ haloalkyl, aryl, heteroaryl, OR⁷, N(R⁷)₂, and SR⁷where said aryl or heteroaryl can be substituted with one or moresubstituents selected from the group consisting of halo, C₁₋₄ alkyl,C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄haloalkoxy, C₁₋₄ alkoxyalkyl, CN, and NO₂;

R⁷ is selected from the group consisting of H, C₁₋₄ alkyl, C₂₋₄ alkenyl,and C₂₋₄ alkynyl, C₁₋₄ haloalkyl, aryl, and heteroaryl, where said arylor heteroaryl can be substituted with one or more substituents selectedfrom the group consisting of halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₁₋₄ alkoxyalkyl,CN, and NO₂;

A is selected from the group consisting of aryl or heteroaryl, wheresaid aryl and heteroaryl can be substituted with one or moresubstituents selected from the group consisting of halo, C₁₋₄ alkyl,C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄haloalkoxy, C₁₋₄ alkoxyalkyl, C₁₋₄ alkoxyalkoxy, CN, NO₂, OH, SCN,C(═O)R⁶, C(═NR⁶)R⁶, S(O_(n))R⁶ where n=0, 1 or 2, aryl, aryloxy,substituted aryloxy, heteroaryl, and heteroaryloxy; and

Z is selected from the group consisting of C(═O)R⁶, C(═S)R⁶, P(═O)(R⁶)₂,and P(═S)(R⁶)₂.

The compounds of Formula One have two chiral centers and can thus existas mixtures of enantiomers and diastereomers. Where the stereochemistryis known, it is designated in the structure. This invention claims thepure enantiomers and diastereomers as well as the mixtures.

In general, these compounds can be used in a variety of ways. Thesecompounds are preferably applied in the form of a formulation comprisingone or more of the compounds with a phytologically acceptable carrier.Concentrated formulations can be dispersed in water, or another liquid,for application, or formulations can be dust-like or granular, which canthen be applied without further treatment. The formulations are preparedaccording to procedures which are conventional in the agriculturalchemical art, but which are novel and important because of the presencetherein of one or more of the compounds.

The formulations that are applied most often are aqueous suspensions oremulsions. Either such water-soluble, water suspendable, or emulsifiableformulations are solids, usually known as wettable powders, or liquids,usually known as emulsifiable concentrates, aqueous suspensions, orsuspension concentrates. The present invention contemplates all vehiclesby which one or more of the compounds can be formulated for delivery anduse as a fungicide.

As will be readily appreciated, any material to which these compoundscan be added may be used, provided they yield the desired utilitywithout significant interference with the activity of these compounds asantifungal agents.

Wettable powders, which may be compacted to form water dispersiblegranules, comprise an intimate mixture of one or more of the compounds,an inert carrier and surfactants. The concentration of the compound inthe wettable powder is usually from about 10% to about 90% w/w, morepreferably about 25% to about 75% w/w. In the preparation of wettablepowder formulations, the compounds can be compounded with any of thefinely divided solids, such as prophyllite, talc, chalk, gypsum,Fuller's earth, bentonite, attapulgite, starch, casein, gluten,montmorillonite clays, diatomaceous earths, purified silicates or thelike. In such operations, the finely divided carrier is ground or mixedwith the compounds in a volatile organic solvent. Effective surfactants,comprising from about 0.5% to about 10% of the wettable powder, includesulfonated lignins, naphthalenesulfonates, alkylbenzenesulfonates, alkylsulfates, and nonionic surfactants, such as ethylene oxide adducts ofalkyl phenols.

Emulsifiable concentrates of the compounds comprise a convenientconcentration, such as from about 10% to about 50% w/w, in a suitableliquid. The compounds are dissolved in an inert carrier, which is eithera water miscible solvent or a mixture of water-immiscible organicsolvents, and emulsifiers. The concentrates may be diluted with waterand oil to form spray mixtures in the form of oil-in-water emulsions.Useful organic solvents include aromatics, especially the high-boilingnaphthalenic and olefinic portions of petroleum such as heavy aromaticnaphtha. Other organic solvents may also be used, such as, for example,terpenic solvents, including rosin derivatives, aliphatic ketones, suchas cyclohexanone, and complex alcohols, such as 2-ethoxyethanol.

Emulsifiers which can be advantageously employed herein can be readilydetermined by those skilled in the art and include various nonionic,anionic, cationic and amphoteric emulsifiers, or a blend of two or moreemulsifiers. Examples of nonionic emulsifiers useful in preparing theemulsifiable concentrates include the polyalkylene glycol ethers andcondensation products of alkyl and aryl phenols, aliphatic alcohols,aliphatic amines or fatty acids with ethylene oxide, propylene oxidessuch as the ethoxylated alkyl phenols and carboxylic esters solubilizedwith the polyol or polyoxyalkylene. Cationic emulsifiers includequaternary ammonium compounds and fatty amine salts. Anionic emulsifiersinclude the oil-soluble salts (e.g., calcium) of alkylaryl sulphonicacids, oil soluble salts or sulphated polyglycol ethers and appropriatesalts of phosphated polyglycol ether.

Representative organic liquids which can be employed in preparing theemulsifiable concentrates of the present invention are the aromaticliquids such as xylene, propyl benzene fractions; or mixed naphthalenefractions, mineral oils, substituted aromatic organic liquids such asdioctyl phthalate; kerosene; dialkyl amides of various fatty acids,particularly the dimethyl amides of fatty glycols and glycol derivativessuch as the n-butyl ether, ethyl ether or methyl ether of diethyleneglycol, and the methyl ether of triethylene glycol. Mixtures of two ormore organic liquids are also often suitably employed in the preparationof the emulsifiable concentrate. The preferred organic liquids arexylene, and propyl benzene fractions, with xylene being most preferred.The surface-active dispersing agents are usually employed in liquidformulations and in the amount of from 0.1 to 20 percent by weight ofthe combined weight of the dispersing agent with one or more of thecompounds. The formulations can also contain other compatible additives,for example, plant growth regulators and other biologically activecompounds used in agriculture.

Aqueous suspensions comprise suspensions of one or more water-insolublecompounds, dispersed in an aqueous vehicle at a concentration in therange from about 5% to about 50% w/w. Suspensions are prepared by finelygrinding one or more of the compounds, and vigorously mixing the groundmaterial into a vehicle comprised of water and surfactants chosen fromthe same types discussed above. Other ingredients, such as inorganicsalts and synthetic or natural gums, may also be added to increase thedensity and viscosity of the aqueous vehicle. It is often most effectiveto grind and mix at the same time by preparing the aqueous mixture andhomogenizing it in an implement such as a sand mill, ball mill, orpiston-type homogenizer.

The compounds may also be applied as granular formulations, which areparticularly useful for applications to the soil. Granular formulationsusually contain from about 0.5% to about 10% w/w of the compounds,dispersed in an inert carrier which consists entirely or in large partof coarsely divided attapulgite, bentonite, diatomite, clay or a similarinexpensive substance. Such formulations are usually prepared bydissolving the compounds in a suitable solvent and applying it to agranular carrier which has been preformed to the appropriate particlesize, in the range of from about 0.5 to about 3 mm. Such formulationsmay also be prepared by making a dough or paste of the carrier and thecompound, and crushing and drying to obtain the desired granularparticle.

Dusts containing the compounds are prepared simply by intimately mixingone or more of the compounds in powdered form with a suitable dustyagricultural carrier, such as, for example, kaolin clay, ground volcanicrock, and the like. Dusts can suitably contain from about 1% to about10% w/w of the compounds.

The formulations may contain adjuvant surfactants to enhance deposition,wetting and penetration of the compounds onto the target crop andorganism. These adjuvant surfactants may optionally be employed as acomponent of the formulation or as a tank mix. The amount of adjuvantsurfactant will vary from 0.01 percent to 1.0 percent v/v based on aspray-volume of water, preferably 0.05 to 0.5%. Suitable adjuvantsurfactants include ethoxylated nonyl phenols, ethoxylated synthetic ornatural alcohols, salts of the esters or sulphosuccinic acids,ethoxylated organosilicones, ethoxylated fatty amines and blends ofsurfactants with mineral or vegetable oils.

The formulations may optionally include combinations that can compriseat least 1% of one or more of the compounds with another pesticidalcompound. Such additional pesticidal compounds may be fungicides,insecticides, nematocides, miticides, arthropodicides, bactericides orcombinations thereof that are compatible with the compounds of thepresent invention in the medium selected for application, and notantagonistic to the activity of the present compounds. Accordingly, insuch embodiments the other pesticidal compound is employed as asupplemental toxicant for the same or for a different pesticidal use.The compounds and the pesticidal compound in the combination cangenerally be present in a weight ratio of from 1:100 to 100:1

The present invention includes within its scope methods for the controlor prevention of fungal attack. These methods comprise applying to thelocus of the fungus, or to a locus in which the infestation is to beprevented (for example applying to cereal or grape plants), a fungicidalamount of one or more of the compounds. The compounds are suitable fortreatment of various plants at fungicidal levels, while exhibiting lowphytotoxicity. The compounds are useful in a protectant or eradicantfashion. The compounds are applied by any of a variety of knowntechniques, either as the compounds or as formulations comprising thecompounds. For example, the compounds may be applied to the roots, seedsor foliage of plants for the control of various fungi, without damagingthe commercial value of the plants. The materials are applied in theform of any of the generally used formulation types, for example, assolutions, dusts, wettable powders, flowable concentrates, oremulsifiable concentrates. These materials are conveniently applied invarious known fashions.

The compounds have been found to have significant fungicidal effectparticularly for agricultural use. Many of the compounds areparticularly effective for use with agricultural crops and horticulturalplants, or with wood, paint, leather or carpet backing.

In particular, the compounds effectively control a variety ofundesirable fungi that infect useful plant crops. Activity has beendemonstrated for a variety of fungi, including for example the followingrepresentative fungi species: Downy Mildew of Grape (Plasmoparaviticola—PLASVI); Late Blight of Tomato and Potato (Phytophthorainfestans—PHYTIN); Brown Rust of Wheat (Puccinia recondita—PUCCRT);Powdery Mildew of Wheat (Erysiphe graminis—ERYSGT); Leaf Blotch of Wheat(Septoria tritici—SEPTTR); Sheath Blight of Rice (Rhizoctoniasolani—RHIZSO); and Glume Blotch of Wheat (Septoria nodorum—LEPTNO). Itwill be understood by those in the art that the efficacy of the compoundfor the foregoing fungi establishes the general utility of the compoundsas fungicides.

The compounds have broad ranges of efficacy as fungicides. The exactamount of the active material to be applied is dependent not only on thespecific active material being applied, but also on the particularaction desired, the fungal species to be controlled, and the stage ofgrowth thereof, as well as the part of the plant or other product to becontacted with the compound. Thus, all the compounds, and formulationscontaining the same, may not be equally effective at similarconcentrations or against the same fungal species.

The compounds are effective in use with plants in a disease inhibitingand phytologically acceptable amount. The term “disease inhibiting andphytologically acceptable amount” refers to an amount of a compound thatkills or inhibits the plant disease for which control is desired, but isnot significantly toxic to the plant. This amount will generally be fromabout 1 to about 1000 ppm, with 10 to 500 ppm being preferred. The exactconcentration of compound required varies with the fungal disease to becontrolled, the type of formulation employed, the method of application,the particular plant species, climate conditions, and the like. Asuitable application rate is typically in the range from about 0.10 toabout 4 pounds/acre (about 0.1 to 0.45 grams per square meter g/m²).

EXAMPLES

These examples are provided to further illustrate the invention. Theyare not meant to be construed as limiting the invention.

Preparation of the Inventive Compounds

The claimed materials have been prepared by several methods that aredescribed below. In general, the desired final product is prepared bythe coupling of an electrophile with a sulfur nucleophile, followed byoxidation of the sulfur to the sulfone. The sulfur may be on either theamine half of the molecule or on the arylalkyl half, as shown in FIG. 1below. The electrophilic and nucleophilic reactants may be prepared asshown in FIG. 1 by conventional methods well known to those skilled inthe art.

(a. Carlson, R. M.; Lee, S. Y. Tetrahedron Lett. 1969, 4001. b.Rosenthal, D. et al. J. Org. Chem. 1965, 30, 3689. c. Mezo, G.; Mihala,N.; Koczan, B.; Hudecz, F. Tetrahedron 1998, 54, 6757. d. Boerner, A.;Voss, G. Synthesis 1990, 573.)

These two halves are coupled, the amine is acylated if necessary, andthe sulfur is oxidized as is shown in FIG. 2

Preparation of Compound 21 by the Use of Thiol Nucleophile and PhenylElectrophile

A solution of 1.55 g of (S)-2-valinethiol nucleophile in 10 mL dry DMFwas purged with nitrogen for 10 minutes. To this was added 20 mL of 1Mpotassium t-butoxide in THF, followed immediately by 2.20 g of the1-(4-bromophenyl)chloroethane electrophile. The mixture was allowed tostir for 20 minutes, and then partitioned between water andether/hexanes (1:1). The aqueous phase was extracted twice more and theorganic phases washed with brine, dried, and solvent removed on therotovap to give a pale oil. This could be purified by evaporativedistillation, but was normally used as is. A solution of 1.21 g of theabove crude product in 30 mL of dichloromethane was cooled in an icebath and then a 20 mol % excess of 3-butyn-1-yl chloroformate (preparedby the action of 3 equivalents of phosgene as a 20% solution in tolueneon the alcohol for 3-4 hours, followed by evaporation to remove toluene)was added, followed by 10 mL of saturated aqueous sodium bicarbonatesolution. The two-phase mixture was vigorously stirred for 30 minutes,then the phases were separated, organic phase dried and diluted to 40 mLvolume with dichloromethane. This was cooled in an ice bath, then 1.73 gm-chloroperbenzoic acid was added in portions with stirring, and themixture stirred for 4-5 hours below 5° C. Sufficient 1.5M sodiumthiosulfate solution was added to quench excess oxidant and then themixture basicified with 2N sodium hydroxide. The phases were separated,and the organic phase dried, rotovapped, and the crude product purifiedby chromatography to give sulfone 21 as 1.42 g of white foam, 96% pureby GLC.

Preparation of Compound 4 by Use of Thiol Nucleophile and TosylateElectrophile

A solution of 354 mg of 1-(4-trifluoromethoxyphenyl)ethanethiol wasadded to a nitrogen purged suspension of 1 equivalent of sodium hydridein 20 mL of dry tetrahydrofuran (THF) and stirred to give a clearsolution. To this was added 500 mg of (S)-isopropoxycarbonylvalinoltosylate, and the mixture was stirred overnight at room temperature. Thereaction was worked up and oxidized in the same manner as the methodused for compound 21 above, purified by chromatography to give 269 mgwhite solid. MP 50-60° C.

By the above two methods, one can prepare most compounds of the typeclaimed, including compounds 1-43, except for compounds 11, 12, and 15which were prepared from compound 1 by methods to be described below,and compound 22 whose preparation is also described below. The firstdescribed method is in general most useful.

The phenyl electrophiles used can be prepared as shown in FIG. 3.

The reduction of acetophenones to alcohols and the conversion of thesealcohols by either the use of concentrated hydrochloric acid neat orthionyl chloride in methylene chloride are well known by those practicedin the art. (Larock, R. C. Comprehensive Organic Transformations: aGuide to Functional Group Preparations; VCH Publishers, Inc.: New York,New York, 1989; p. 529, 354-355.) The electrophiles used to preparecompounds 1-43, (except for compounds 8, 10-12, 15, and 26) wereprepared by this method.

The radical bromination of arylethanes using N-bromosuccinimide and UVlight to make 1-bromo-1-arylethanes is also well known, (Djerassi, C;Chem. Rev. 1948, 43, 271) and this method was used to prepareelectrophiles for compounds 8 and 10.

The phenyl electrophiles discussed above could be transformed into thiolnucleophiles by the well described use of xanthate salts as shown inFIG. 4. (Degani, I.; Fochi, R. Synthesis 1978, 365) These nucleophilescan be used with the tosylate electrophile to prepare many of theinventive materials.

Compound 1 was converted into compound 11, and this material was used toprepare compounds 15 and 12 as shown in FIG. 5. All of the steps shownin FIG. 5 are well known to those in the art. (Morris, J.; Wishka, D. G.J. Org. Chem. 1991, 56, 3549.)

Compound 22 was prepared as shown in FIG. 6, and described in thepreparation below.

Preparation of isopropyl1-({[chloro(4-chlorophenyl)methyl]sulfonyl}methyl)-2-methylpropylcarbamate(Compound 22)

To 88 mg of 60% sodium hydride in dry THF:DMF (4:1) under nitrogenatmosphere was added 350 mg of 4-chlorobenzylthiol, and the mixturestirred to give a clear solution. To this was added 686 mg of thetosylate electrophile, and the reaction was stirred for 3 hours at roomtemperature. The reaction was partitioned between 0.1N HCl and ether,aqueous extracted twice with ether, and the combined organic phaseswashed twice with brine. The ether phase was dried and evaporated, andthe crude product purified by flash chromatography. To 385 mg of thismaterial in 10 mL of dry THF at −78° C. was added 500 μL of 2.5Mn-butyllithium in hexanes over 5 minutes, followed after 5 minutes by281 mg of di-t-butyl dicarbonate in 2 mL of THF. The reaction wasallowed to warm to room temperature and stirred for 4 hours, then workedup as above and the crude sulfide product purified by flashchromatography to give 245 mg of nearly colorless, viscous oil, pure byTLC and ¹H NMR. To a solution of the above sulfide in 10 mL of methylenechloride, cooled in an ice-bath, was added a solution of 83 mg ofN-chlorosuccinimide in 3 mL of methylene chloride over 5 minutes. Thesolution was stirred for 4 hours as it warmed to room temperature. Tothis solution was added 300 mg of MCPBA, and the reaction was stirred anadditional 2 hours. The excess oxidant was quenched with sodiumthiosulfate solution, then basified with 2N sodium hydroxide. The phaseswere separated, the organic phase was dried, and solvent removed on therotovap. The residue was dissolved in 5 mL of methylene chloride andcooled to 10° C., and then 2 mL of TFA was added, followed by stirringovernight. The solvents were removed on the rotovap and the residuepurified by flash chromatography to give 80 mg of a white solid.

Compound 26 was prepared using selective alkylation conditions on thesulfone shown in FIG. 7. (Wada, A.; Tode, C.; Hiraishi, S.; Tanaka, Y.;Ohfusa, T.; Ito, M. Synthesis 1995, 1107.) The BOC group was removed andreplaced with an aromatic carbamate using procedures previouslydescribed.

Compounds 32-34 were prepared by reaction of an isocyanate with theappropriate aromatic alcohol as shown in FIG. 8. (Blahak, J. Ann. Chem.1978,1353.)

Compound 37 was likewise generated from the amine salt and anappropriately substituted phenyl isocyanate as shown in FIG. 9. (Gaudry,R. Can J. Chem. 1951, 29, 544)

Compound 44 was prepared in 8 steps from valine methyl ester utilizingamino acid chemistry (a. Overhand, M.; Hecht, S. M. J. Org. Chem. 1994,59, 4721. B. Son, Y. C.; Park, C. H.; Koh, J. S.; Choy, N. Y.; Lee, C.S.; Choi, H.; Kim, S. C.; Yoon, H. S. Tetrahedron Lett. 1994, 35, 3745.C. Nacci, V.; Campiani, G.; Garofalo, A. Synth. Commun. 1990, 20, 3019.)combined with coupling and oxidation chemistry described above.

In Table 1, “EA” stands for elemental analysis.

TABLE 1 PHYSICAL DATA FOR SELECTED COMPOUNDS Compound Number Physicalstate MP MS NMR EA 1 white solid 60-70 X X 2 white solid 110-120 X X 3gum 4 white solid 50-60 X X 5 white solid 75-85 X X 6 tan solid 416 (M− 1) 7 white foam 416 (M − 1) X X 8 white foam X X 9 gum 371 (M − 1) 10white solid X X 11 pale yellow 125-135 X X solid 12 sticky white X foam13 white solid X X 14 white solid 140-145 X X 15 white solid 50-60 X X16 tan solid 390 (M − 1) 17 white foam 55-65 X X 18 white foam 419 (M+)X 19 white foam 415 (M + 1) X X 20 clear glass X 21 white foam X X 22white solid 140-143 X 23 viscous gum X X 24 off-white 465 (M+) X stickysolid 25 yellow foam X 26 colorless oil 441 (M+) X 27 white foam 457(M + 1) X 28 white glass X X 29 white solid 65-74 415 (M + 1) X X 30white foam 479 (M + 1) X X 31 white powder 129-135 504 (M + 1) X X 32white solid 500/502 (M + 1) X 33 white foam 429 (M + 1) X X 34 whitefoam 480 (M + 1) X 35 yellow foam 383 (M + 1) X 36 clear glass 369(M + 1) X 37 white glass 468 (M + 1) X X 38 white powder 50-60 401(M + 1) X 39 glass 435 (M + 1) X 40 waxy 431 (M + 1) X white solid 41white crystals 58-65 X 42 white foam 50-62 405 (M + 1) X 43 white foam50-53 431 (M + 1) X 44 clear oil 435 (M+) X

Biological Testing

The compounds were formulated at 100 ppm in 10 vol % acetone plus 90 vol% Triton X water (deionized water 99.99 wt % +0.01 wt % Triton X100).The compounds were tested for ability to control plant diseases at thewhole plant level in a 1-day protectant test (1 DP). Chemicals weresprayed on a turn table sprayer fitted with two opposing air atomizationnozzles which delivered approximately 1500 L/ha of spray volume. Plantswere inoculated with spores of the fungus the next day, then incubatedin an environment conducive to disease development. Disease severity wasevaluated 4 to 19 days later, depending on the speed of diseasedevelopment.

The following experiments were performed in the laboratory to determinethe fungicidal efficacy of the compounds of the invention.

Late Blight of Tomatoes (Phytophthora infestans—PHYTIN): Tomatoes(cultivar Rutgers) were grown from seed in a soilless peat-based pottingmixture (Metromix) until the seedlings were 1-2 leaf (BBCH 12). Theseplants were then sprayed to run off with the formulated test compound ata rate of 100ppm. After 24 hours the test plants were inoculated with anaqueous spore suspension of Phytophthora infestans and incubatedovernight in a dew chamber. The plants were then transferred to thegreenhouse until disease developed on the untreated control plants.

Downy Mildew of Grapes (Plasmopara viticola—PLASVI): Grape plants(variety ‘Carignane’) were grown from seed in a greenhouse for six weeksin a soil-less potting mix until the seedlings were at a 2 to 3-leafstage. These plants were sprayed to runoff with the formulated testcompound at a rate of 100 ppm. After 24 hours the undersides of theleaves were inoculated with an aqueous spore suspension of Plasmoparaviticola and the plants were kept in high humidity overnight. The plantswere then transferred to a greenhouse until disease developed onuntreated control plants.

Leaf Blotch of Wheat (Septoria tritici—SEPTTR): Wheat plants (varietyMonon) were grown from seed in a greenhouse in 50% pasteurized soil/50%soil-less mix until the first true leaf was fully expanded, with 6-8seedlings per pot. These plants were sprayed to runoff with theformulated test compound at a rate of 100 ppm. After 24 hours the leaveswere inoculated with an aqueous spore suspension of Septoria tritici andthe plants were kept in high humidity overnight. The plants were thentransferred to a greenhouse until disease developed on untreated controlplants.

The following table presents the activity of typical compounds of thepresent invention when evaluated in these experiments. The effectivenessof the test compounds in controlling disease was rated by giving thepercent control of the plant disease compared with untreated, inoculatedplants.

TABLE 2 Fungicidal activity of compounds on plant diseases in greenhousetests. Ratings are percent control in a one-day protectant test. (−≦20%, + = 20-49%, ++ = 50-89%, +++ = 90-100%, NT = not tested). CompoundNumber Compound PHYTIN PLASVI SEPTTR 1

+++ +++ − 2

+++ +++ − 3

+++ ++ NT 4

+++ +++ − 5

+++ ++ − 6

+++ +++ NT 7

+++ ++ + 8

++ ++ − 9

+++ +++ NT 10

+++ +++ NT 11

+++ ++ ++ 12

+++ +++ NT 13

+++ +++ − 14

+++ +++ NT 15

+++ +++ NT 16

+++ ++ NT 17

+++ +++ + 18

+++ +++ ++ 19

+++ +++ NT 20

+++ ++ + 21

+++ ++ ++ 22

+++ +++ − 23

++ ++ ++ 24

+++ +++ NT 25

+++ +++ NT 26

+++ +++ NT 27

+++ +++ ++ 28

+++ +++ NT 29

+++ +++ ++ 30

+++ +++ NT 31

+++ +++ NT 32

+++ +++ NT 33

+++ +++ NT 34

+++ +++ NT 35

+++ +++ NT 36

++ ++ NT 37

+++ +++ NT 38

+++ +++ NT 39

+++ +++ NT 40

+++ +++ NT 41

++ +++ NT 42

+++ +++ NT 43

++ +++ NT 44

+++ ++ NT

We claim:
 1. A compound according to formula one

wherein: R¹ is selected from the group consisting of F, Cl, Br, CN, C₁₋₄alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxyalkyl,C₃-C₆ cycloalkyl, C₃-C₆ cycloalkenyl, CH₂(C═O)R⁵, and CH₂CN; R² and R³are selected from the group consisting of H, CH₃, F, and Cl; R⁴ isselected from the group consisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkenyl, aryl, and heteroaryl, wheresaid alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl, can besubstituted with one or more substituents selected from the groupconsisting of halo, C₁₋₄ alkoxy, C₃₋₆ cycloalkyl, aryl and heteroaryl,and where said aryl and heteroaryl can be substituted with one or moresubstituents selected from the group consisting of halo, C₁₋₄ alkyl,C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄haloalkoxy, C₁₋₄ alkoxyalkyl, C₁₋₄ alkoxyalkoxy, CN, NO₂, OH, SCN,C(═O)R⁶, C(═NR⁶)R⁶, S(O_(n))R⁶ where n=0, 1 or 2, aryl, aryloxy,heteroaryl, and heteroaryloxy; R⁵ is selected from the group consistingof H, OR⁷, and C₁₋₄ alkyl; R⁶ is selected from the group consisting ofH, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl,aryl, heteroaryl, OR⁷, N(R⁷)₂, and SR⁷ where said aryl or heteroaryl canbe substituted with one or more substituents selected from the groupconsisting of halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ alkoxy,C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₁₋₄ alkoxyalkyl, CN, and NO₂; R⁷ isselected from the group consisting of H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, C₁₋₄ haloalkyl, aryl and heteroaryl, where said aryl orheteroaryl can be substituted with one or more substituents selectedfrom the group consisting of halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₁₋₄ alkoxyalkyl,CN, and NO₂; A is selected from the group consisting of aryl orheteroaryl, where said aryl and heteroaryl can be substituted with oneor more substituents selected from the group consisting of halo, C₁₋₄alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄haloalkoxy, C₁₋₄ alkoxyalkyl, C₁₋₄ alkoxyalkoxy, CN, NO₂, OH, SCN,C(═O)R⁶, C(═NR⁶)R⁶, S(O_(n))R⁶ where n=0, 1 or 2, aryl, aryloxy,substituted aryloxy, heteroaryl, and heteroaryloxy; and Z is selectedfrom the group consisting of C(═O)R⁶, C(═S)R⁶, P(═O)(R⁶)₂, andP(═S)(R⁶)₂.
 2. A compound according to claim 1 wherein: R¹ is selectedfrom the group consisting of Cl, C₁₋₄ alkyl, and C₂₋₄ alkenyl; R² and R³are selected from the group consisting of H and CH₃; R⁴ is a C₁₋₆ alkylwhere said alkyl, can be substituted with one or more C₁₋₄ alkoxysubstituents; R⁵ is H; R⁶ is selected from the group consisting of H,C₁₋₄ alkoxy, OR⁷, N(R⁷)₂, and SR⁷; R⁷ is selected from the groupconsisting of H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl,aryl, and heteroaryl, where said aryl or heteroaryl can be substitutedwith one or more substituents selected from the group consisting ofhalo, CN, C₁₋₄ alkyl, and C₁₋₄ alkoxy; A is selected from the groupconsisting of aryl or heteroaryl, where said aryl and heteroaryl can besubstituted with one or more substituents selected from the groupconsisting of halo, CN, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, aryl, substitutedaryloxy, C₂₋₄ alkenyl, C(═NR⁶)R⁶, NO₂, and C(═O)R⁶; and Z is selectedfrom the group consisting of C(═O)R⁶ and C(═S)R⁶.
 3. A compoundaccording to claim 2 wherein: A is selected from the group consisting ofaryl or heteroaryl, where said aryl and heteroaryl is substituted withone substituent selected from the group consisting of Br and CN; and Zis selected from the group consisting of isopropyl and C(═O)R⁶, wheresaid R⁶ is OR⁷, and where said R⁷ is selected from the group consistingof aryl and heteroaryl, where said aryl or heteroaryl is substitutedwith one substituent selected from the group consisting of halo andmethyl.
 4. A compound according to claim 3 wherein the substituent on Ais in the para position and wherein Z is C(═O)R⁶, where said R⁶ is OR⁷,and where said R⁷ is selected from the group consisting of aryl andheteroaryl, where said aryl or heteroaryl is substituted with onesubstituent selected from the group consisting of halo and methyl, whichis in the para position.
 5. A compound according to claim 1 wherein: R¹is selected from the group consisting of Cl and methyl; R² and R³ is H;R⁴ is a C₁₋₆ alkyl; R⁵ is H; R⁶ is selected from the group consisting ofH, methoxy, and OR⁷; R⁷ is selected from the group consisting of C₁₋₄alkyl, C₂₋₄ alkynyl, aryl where said aryl can be substituted with one ormore substituents selected from the group consisting of halo and methyl;A is selected from the group consisting of aryl or heteroaryl, wheresaid aryl and heteroaryl can be substituted with one or moresubstituents selected from the group consisting of halo, CN, C₁₋₄alkoxy, C₁₋₄ haloalkoxy, aryl, substituted aryloxy, C₂₋₄ alkynyl,C(═NR⁶)R⁶, NO₂, and C(═O)R⁶; and Z is C(═O)R⁶ where said R⁶ is OR⁷.
 6. Acompound according to claim 5 wherein: A is selected from the groupconsisting of aryl or heteroaryl, where said aryl and heteroaryl issubstituted with one substituent selected from the group consisting ofBr and CN; and Z is selected from the group consisting of isopropyl andC(═O)R⁶ where said R⁶ is OR⁷, and where said R⁷ is selected from thegroup consisting of aryl and heteroaryl, where said aryl or heteroarylis substituted with one substituent selected from the group consistingof halo and methyl.
 7. A compound according to claim 6 wherein thesubstituent on A is in the para position and wherein Z is C(═O)R⁶, wheresaid R⁶ is OR⁷, and where said R⁷ is selected from the group consistingof aryl and heteroaryl, where said aryl or heteroaryl is substitutedwith one substituent selected from the group consisting of halo andmethyl, which is in the para position.
 8. A process to control orprevent a fungal attack said process comprising applying to a locus afungicidal amount of one or more of the compounds according to claim 1.9. A process to control or prevent a fungal attack said processcomprising applying to a locus a fungicidal amount of one or more of thecompounds according to claim
 2. 10. A process to control or prevent afungal attack said process comprising applying to a locus a fungicidalamount of one or more of the compounds according to claim
 3. 11. Aprocess to control or prevent a fungal attack said process comprisingapplying to a locus a fungicidal amount of one or more of the compoundsaccording to claim
 4. 12. A process to control or prevent a fungalattack said process comprising applying to a locus a fungicidal amountof one or more of the compounds according to claim
 5. 13. A process tocontrol or prevent a fungal attack said process comprising applying to alocus a fungicidal amount of one or more of the compounds according toclaim
 6. 14. A process to control or prevent a fungal attack saidprocess comprising applying to a locus a fungicidal amount of one ormore of the compounds according to claim
 7. 15. A composition comprisinga disease inhibiting and phytologically acceptable amount of a compoundaccording to claim 1 and at least one additional pesticidal compoundselected from the group consisting of fungicides, insecticides,nematocides, miticides, arthropodicides, and bactericides.
 16. Acomposition comprising a disease inhibiting and phytologicallyacceptable amount of a compound according to claim 2 and at least oneadditional pesticidal compound selected from the group consisting offungicides, insecticides, nematocides, miticides, arthropodicides, andbactericides.
 17. A composition comprising a disease inhibiting andphytologically acceptable amount of a compound according to claim 3 andat least one additional pesticidal compound selected from the groupconsisting of fungicides, insecticides, nematocides, miticides,arthropodicides, and bactericides.
 18. A composition comprising adisease inhibiting and phytologically acceptable amount of a compoundaccording to claim 4 and at least one additional pesticidal compoundselected from the group consisting of fungicides, insecticides,nematocides, miticides, arthropodicides, and bactericides.
 19. Acomposition comprising a disease inhibiting and phytologicallyacceptable amount of a compound according to claim 5 and at least oneadditional pesticidal compound selected from the group consisting offungicides, insecticides, nematocides, miticides, arthropodicides, andbactericides.
 20. A composition comprising a disease inhibiting andphytologically acceptable amount of a compound according to claim 6 andat least one additional pesticidal compound selected from the groupconsisting of fungicides, insecticides, nematocides, miticides,arthropodicides, and bactericides.
 21. A composition comprising adisease inhibiting and phytologically acceptable amount of a compoundaccording to claim 7 and at least one additional pesticidal compoundselected from the group consisting of fungicides, insecticides,nematocides, miticides, arthropodicides, and bactericides.
 22. A processcomprising reacting the appropriate electrophile with the appropriatesulfur nucleophile to produce a compound according to claim
 1. 23. Aprocess comprising reacting the appropriate electrophile with theappropriate sulfur nucleophile to produce a compound according to claim2.
 24. A process comprising reacting the appropriate electrophile withthe appropriate sulfur nucleophile to produce a compound according toclaim
 3. 25. A process comprising reacting the appropriate electrophilewith the appropriate sulfur nucleophile to produce a compound accordingto claim
 4. 26. A process comprising reacting the appropriateelectrophile with the appropriate sulfur nucleophile to produce acompound according to claim
 5. 27. A process comprising reacting theappropriate electrophile with the appropriate sulfur nucleophile toproduce a compound according to claim
 6. 28. A process comprisingreacting the appropriate electrophile with the appropriate sulfurnucleophile to produce a compound according to claim 7.